Surgical sutures of unsymmetrically substituted 1,4-dioxane-2,5-diones

ABSTRACT

Unsymmetrically 3,6-substituted 1,4-dioxane-2,5-diones may be polymerized to give living-tissue absorbable, hydrolytically degradable surgically useful polymers. These polymers have predominantly regular rather than random spacings of side chains, may be stereoregular and tend toward higher crystallinity than randomly sequenced polymers. A polymer of 3-methyl-1,4-dioxane-2,5-dione has the same empirical formula as an equimolecular copolymer of lactic and glycolic acid but has unique physical properties resulting from its more regular steric configuration. Polymers and copolymers of 3- and 3,6-unsymmetrically substituted 1,4-dioxane-2,5-diones have surgically useful mechanical properties. On implantation, in living mammalian tissue, the polymers are absorbed, and replaced by living tissue.

This is a Division of the Application Ser. No. 435,365, filed Jan. 21,1974, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to unsymmetrically substituted1,4-dioxane-2,5-diones, methods of making them, and more particularly topolymers, which polymers are either homopolymers of the unsymmetricallysubstituted 1,4-dioxane-2,5-diones or copolymers, and which polymers arecompatible with living mammalian tissue, particulary human tissue, andwhich materials can be surgically and are biologically degradable intotissue compatible components which are absorbed by living tissues. It ispresently postulated that the primary degradation of the polymer is byhydrolytic fission into products which can be carried away by the livingtissue and which products are degradable to excretable components or arethemselves excretable. Because of the surgical demand fr sutures,absorbable fabrics, gauzes, bone pins, etc. whose absorption andstrength characteristics vary, it is desirable that a spectrum ofstrength and absorbability be provided to meet surgical demands forvarious procedures.

DESCRIPTION OF THE PRIOR ART

U.S. Pat. No. 2,518,456, Fein and Fisher, Aug. 15, 1950, PREPARATION OFACYLOXY CARBOXYLIC ACIDS FROM ESTERS OF HYDROXY CARBOXYLIC ACIDS,discloses preparing ##EQU1## there called chloroacetoxypropionic acid(which may be also properly named as O-(chloroacetyl)-lactic acid orα-(chloro-acetoxy)-propionic acid) by transesterification using an acidcatalyst such as concentrated sulfuric acid with chloroacetic acid andethyl lactate.

U.S. Pat. No. 2,676,945, Higgins, Apr. 27, 1954, CONDENSATION POLYMERSOF HYDROXYACETIC ACID, discloses strong orientable fibers ofpolyhydroxyacetic acid condensate (poly-glycolic acid) having anintrinsic viscosity of 0.5 to 1.2.

U.S. Pat. No. 2,758,987, Salzberg, Aug. 14, 1956, OPTICALLY ACTIVEHOMOPOLYMERS CONTAINING BUT ONE ANTIPODAL SPECIES OF ANALPHA-MONOHYDROXY MONOCARBOXYLIC ACID, discloses forming high molecularweight optically active, cold-drawable, polymers from one antipodalspecies of alpha-hydroxypropionic acid (lactic acid).

U.S. Pat. No. 3,268,487, Klootwijk, Aug. 23, 1966, PROCESS FORPOLYMERIZATION OF LACTIDES, discloses catalyst system and thepolymerization of symmetrical lactides to give polymers with therecurring unit ##EQU2## where R¹ and R² are hydrogen atoms or alkyl,cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, phenol, alkaryl,hydroxyphenyl, or haloaryl radicals. Copolymers, including blockcopolymers are shown. (Col. 1, lines 57-66).

U.S. Pat. No. 3,297,033, Schmitt and Polistina, January 10, 1967,SURGICAL SUTURES, discloses polyhydroxyacetic ester absorbable sutures.The material is also called polyglycolic acid, and is disclosed aspermitting small quantities of comonomers to be present, such asdl-lactic acid, its optically active forms, homologs and analogs. Asmall quantity is recognized by the art as up to 156, as shown by U.S.Pat. No. 2,668,162, Lowe, Feb. 2, 1954, PREPARATION OF HIGH MOLECULARWEIGHT POLYHYDROXY-ACETIC ESTER.

Many uses of polyglycolic acid for surgical purposes are disclosed insaid U.S. Pat. No. 3,297,033 and continuations-in-part thereofincluding: U.S. Pat. No. 3,463,158, Infra; U.S. Pat. No. 3,620,218,Infra; U.S. Pat. No. 3,739,773, June 19, 1973 -- POLYGLYCOLIC PROSTHETICDEVICES and U.S. Ser. No. 365,656, May 31, 1973, SURGICAL DRESSINGS OFABSORBABLE POLYMERS.

U.S. Pat. No. 3,303,177, Natta, Peraldo and Farina, Feb. 7, 1967,SUBSTANTIALLY LINEAR, REGULARLY HEAD-TO-TAIL POLYMERS OF DEUTERATED ANDTRITIATED MONOMERS AND PROCESS FOR PRODUCING THE SAME, discloses theimportant effect of high regularity of steric structure as well as highregularity of chemical structure on the characteristics of polymers. Anomenclature for such polymers is set forth.

U.S. Pat. No. 3,463,158, Schmitt and Polistina, Aug. 26, 1969,POLYGLYCOLIC ACID PROSTHETIC DEVICES, discloses surgical uses ofpolyglycolic acid, and incorporates definitions of some terms.

U.S. Pat. No. 3,492,325, Thompson, Jan. 27, 1970, PRODUCTION OFα-HYDROXY ACIDS AND ESTERS, discloses the conversion of α-keto acetalsinto α-hydroxy acids and esters, including lactides. The lactidesproduced are symmetrical.

U.S. Pat. No. 3,620,218, Schmitt and Polistina, Nov. 16, 1971,CYLINDRICAL PROSTHETIC DEVICES OF POLYGLYCOLIC ACID, lists many surgicaluses of polyglycolic acid.

U.S. Pat. No. 3,626,948, Glick and McPherson, Dec. 14, 1971, "AbsorablePolyglycolic Acid Suture of Enhanced In-Vivo Strength Retention"discloses heating under vacuum, under specified conditions to removevolatile components to give longer in-vivo strength retention topolyglycolic acid surgical protheses, including sutures.

U.S. Pat. No. 3,636,956, Schneider, Jan. 25, 1972, "Polyactide Sutures",discloses polylactides which may contain up to 70 mole percent glycolide(Col. 12, line 4), and mentions other comonomers, including tetramethylglycolide. (Column 2, line 24). Lactide may be considered to be asymmetrical dimethylglycolide. Schneider prefers polylactides of oneantipodal species, usually poly L(-) lactide.

U.S. Pat. No. 3,736,646, Schmitt, et al., June 5, 1973, METHOD OFATTACHING SURGICAL NEEDLES TO MULTIFILAMENT POLYGLYCOLIC ACID ABSORBABLESUTURES, discloses surgical elements of a copolymer containing from 15to 85 mol percent glycolic acid and 85 to 15 mol percent lactic acid.

U.S. Pat. No. 3,763,190, Ross, Barrett, and McDonald, Oct. 2, 1973,PREPARATION OF PURE GLYCOLIDE, discloses the ring closure ofO-chloroacetylglycolic acid as the sodium salt to give glycolide.

Sporzynsi, Kocay and Briscoe, A NEW METHOD OF PREPARING GLYCOLLIDE,Recueil, 68, 613-618, (1949) relates the "thermal decomposition ofsodium chloracetate under reduced pressure in the presence of coppergave glycollide . . ."

Chujo, Kobayashi, Suzuki, Tokuhara and Tanabe RING-OPENINGPOLYMERIZATION OF GLYCOLIDE, Die Makromolekulare Chemie, 100, 262-266,(1967) shows the preparation of glycolide by the elimination of sodiumchloride from sodium monochloroacetate ##EQU3##

The disclosures of the above patents and articles, particularly onmethods of manufacture and purification of components and of surgicaluses for hydrolytically degradable tissue absorbable polymers, arehereby herein incorporated by this reference thereto.

NOMENCLATURE

Hydroxyacetic acid bears the trivial name of glycolic acid.

2-Hydroxypropanoic acid, or α-hydroxypropanoic acid bears the trivialname of lactic acid. Lactic acid has the formula CH₃ CHOHCOOH, and hasan asymmetric carbon atom, and, hence, may exist in two differentoptically active forms, commonly called D(-)lactic acid and L(+)lacticacid. Where not otherwise specified or incorporated from context, theterm lactic acid refers to the equimolecular or racemic mixture.

A lactide is defined as the product from the internal cyclicesterification of two molecules of an α-hydroxy alkanoic acid. If theα-hydroxy alkanoic acid is lactic acid, the product is lactide itself,which gives its name to the series. Generically, the reaction is##EQU4## where R₁ and R₂ are each separately hydrogen or alkyl.

From the nature of the reaction, such lactide is essentiallysymmetrical, that is, it has two identical R₁ groups and two identicalR₂ groups on the six-membered ring. The compounds in which R₂ ishydrogen are much the more common.

These compounds may be named by systematic nomenclature, for instance,the lactide of lactic acid, with R₁ being methyl and R₂ being hydrogenis properly named and indexed as 3,6-dimethyl-1,4-dioxane-2,5-dione.

In the present invention, the substitution is not symmetrical and,hence, the products are not properly classed as lactides, but are namedas 3-, or 3,6-substituted 1,4dioxane-2,5-diones.

The simplest, and what can be considered as the parent to the class is3-methyl-1,4-dioxane-2,5-dione, which can be given the trivial name ofmonomethylglycolide. Another name is 3-methyl-2,5-diketo-1,4-dioxane.This compound has part of the attributes of glycolide and some oflactide, but, uniquely, is adapted to give controlled and orderedpolymers which empirically resemble a copolymer of glycolide andlactide, but have an ordered structure imparting unique and desirableproperties.

When glycolide is homopolymerized, the product is called homopolymericpoly(hydroxyacetic acid) or poly(glycolic acid) or polyglycolide. Theindividual units in the polymer chain are oxyacetyl radicals ##EQU5##which may be called glycolic acid residues, or glycolic acid units, orglycolic acid radicals or glycolic acid linkages, even though inpolymerization water is eliminated in forming the resultant polyester.For convenience, the term glycolic acid unit is usually used herein.

Similarly, when lactide is homopolymerized, the product is calledhomopolymeric poly(lactic acid) or poly(alpha-hydroxypropionic acid) orpolylactide. The individual units in the polymer chain are2-oxypropionyl radicals ##EQU6## These can be called lactic acidresidues or lactic acid units, or lactic acid radicals, or lactic acidlinkages.

For convenience, the term lactic acid unit is usually used herein. Thesteric configuration is specified if significant and not apparent fromcontext. The steric configuration of the product is normally that of thestarting materials. If the additional regularity resulting from a singleantipode is desired, an appropriate starting material is selected.

When polymerized into chains, three consecutive glycolic acid units areabbreviated --G--G--G-- and three consecutive lactic acid units areabbreviated --L--L--L--. A regularly alternating polymer of glycolicacid units and lactic acid units is abbreviated --G--L--G--L--G--L--.Other orders are similarly represented by the sequence of capitalletters.

In places, hexafluoroacetone sesquihydrate is abbreviated as HFAS;hexafluoroisopropanol is abbreviated as HIPA; poly(glycolic acid) isabbreviated as PGA and 3-methyl-1,4-dioxane-2,5-dione can be abbreviatedas MDD.

To be consistent, the name O-chloroacetyl-L-lactic acid is used, withD,L- or L or D being so designated where appropriate for the formula##EQU7## Other common names include L-2-(chloroacetoxy)-propionic acidand L-α-(chloroacetoxy)-propionic acid.

In copolymerization of two monomers, depending upon the catalyst usedand reaction conditions, the relative rates of reactivity vary, and oneof the monomers usually tends to polymerize more rapidly then the other.

For example, if an equimolecular mixture of glycolide and lactide ispolymerized, the glycolide tends to link to the growing chains morereadily giving relatively long sequences of glycolic acid units withoccasional short sequences of lactic acid units and as the concentrationof the unreacted components change, the ratio of lactide to glycolideincreases and the polymer being formed may contain more nearly equalnumbers of glycolic acid units and lactic acid units. If thepolymerization is stopped before completion, a disproportionately largeamount of unreacted lactide is present in the reaction vessel. Theoccurrence of pairs of glycolic acid units and pairs of lactic acidunits is basically random in nature with a bias towards thepreponderance of glycolic acid units in the first portions of chainsformed and an increasing proportion of lactic acid unit in thoseportions of the chains last formed.

If carried to completion, the last portions of chains formed arepredominantly of pairs of lactic acid units as a minimum of glycolideremains to link to the chains.

Under the usual conditions of polymerization, a randon ordersignificantly predominates and, hence, the product tends to have more ofan amorphous rather than crystalline character. For crystallinity tooccur, extensive lengths of the chain need steric regularity. Forinstance, a regular brick wall can be easily built in any one of anumber of patterns from ordinary bricks which frequently have a size of2 inches × 4 inches × 8 inches including the mortar. On the other hand,random stones or a multitude of sizes do not so readily lend themselvesto an ordeal structure. Analogously with polymer molecules, if the sidegroups occur in a strictly random sequence, the crystallinity of aproduct is decreased as compared with polymers formed with strictlyregular side group spacing.

The present invention relates to the use of unsymmetrically substituted1,4-dioxane,-2,5-diones which in polymerization gives two differentunits of alpha-hydroxy alkanoic acid precursors, but which are very wellordered.

SUMMARY OF THE INVENTION

This invention relates to unsymmetrically substituted1,4-dioxane-2,5-diones, precursors of such dioxanediones, and polymersformed from such dioxanediones. In the simplest such unsymmetricallysubstituted dioxanedione, 3-methyl-1,4-dioxane-2,5-dione, a lactic acidunit, and a glycolic acid unit, are in effect cyclized together, and inpolymerization, when such a ring is opened and added to a polymer chain,a lactic acid unit and a glycolic acid unit are adjacent in the polymerchain. If the ring opening and addition is strictly uniform, the finalproduct will have regularly alternating lactic acid units and glycolicacid units. If polymerization is random, because there is a glycolicacid unit attached to each lactic acid unit, not more than two glycolicacid units or two lactic acid units will be adjacent in the chainformed.

Because hydrolytic fission of the polymer chain is more probableadjacent a glycolic acid unit, and even more probable between two suchglycolic acid units, a minimum of long blocks of lactic units gives morerapid hydrolytic fission, and polymers having adjacent glycolic acidunits are absorbed by tissue even more rapidly than polymers havingstrictly alternating glycolic acid units and lactic acid units.

Copolymerization of some glycolide with the3-methyl-1,4-dioxane-2,5-dione increases susceptibility to hydrolyticfission.

If polymerization of a mixture of glycolic acid and lactic acid is usedto form a copolymer with removal of water, the sequence of units in thefinal copolymer chain will be somewhat random, with the first portionsformed tending to include more glycolic acid units. Because inpolymerization such chains are not always identical and because of thedifficulty of analysis, it is not always readily possible to ascertainthe exact order in a chain, but the general properties of the polymersare the items of interest and it is found that the additional regularityimparted to the chain by the use of the unsymmetrically substituted1,4-dioxane-2,5-diones results in polymers which are both chemically andsterically more uniform.

The unsymmetrically substituted 1,4-dioxane-2,5-diones of this inventionare of importance in the medical field because their polymers, includinghomopolymers and copolymers with various lactides including glycolideand lactide, are useful as surgical elements as later described, but,additionally, the unsymmetrically substituted 1,4-dioxane-2,5-diones areexcellent weak acidifying agents. They may be used in such materials asbaking powders or for the control of pH in boiler waters. They may alsobe used in non-aqueous systems for the neutralization of alkali. Becausethe side chains may vary from methyl to long chain alkyl, includingbranched chains, unsaturated chains, aryl or aralkyl, and which mayinclude halogen, alkoxy, aryloxy, aralkoxy, ether, ester and amidegroups, as substituents on the side chains, the relative distributionbetween aqueous and solvent components in a system can be varied as wellas water solubility or oil and solvent solubility so that the1,4-dioxane-2,5-dione is distributed in a desired location and alsobecause the size and location of the side chains affects the rate ofhydrolysis, the acidity of the system, the rate of availability of acidcan be varied over wide limits to meet the requirements of a system andthe desires of the operator. The less highly substituted materials areoften preferred for medical uses. The border range of substituentspermits more flexibility in pH control, and in biodegradable polymersfor use in packaging, etc. The use of side chains with unsaturatedlinkages permits cros-linked polymers to be formed. This uniformityresults in greater strength, more crystallinity, and more readilyreproducible and controllable characteristics, which are of interest toa surgeon during use.

By copolymerizing the present 1,4-dioxane-2,5-diones, with eitherglycolide or lactide, the physical properties of the polymer are alteredto more closely resemble that of either polyglycolic acid or polylacticacid respectively and the absorption characteristics may be varied. Thelength of polymer chain, as shown by the inherent viscosity of thepolymer, also is impotant is determining the rate of hydrolyticdegradation in tissues and hence by adjusting both the inherentviscosity and the ratio of components, there is provided a wide range oftissue absorbable surgical components which may be tailored to fit thedesires of a surgeon for a particular procedure.

For many purposes, it is desired that the synthetic tissue absorbablepolymer maintain its strength for from 2-60 days and then degrade and beabsorbed thereafter. Because the disappearance of strength is a gradualfunction, the loss of strength is apt to start very early in the usefullife, but an adequate and useful proportion of strength is maintainedfor a surgically desirable period of time and the ultimate absorption ofthe polymer occurs thereafter. Although the polymers having glycolic andlactic acid units are often preferred, dioxanediones are useful in whichthe substituents are ethyl, propyl, isopropyl, butyl, isobutyl,cyclohexyl and phenyl radicals.

One convenient method of making the unsymmetrically substituted1,4-dioxane-2,5-diones is by the reaction of a substituted acetic acidwith an α-hydroxy carboxylic acid to form an acyloxy acid which is ringclosed to form the 3,6-substituted-1,4-dioxane-2,5-dione or the3-substituted-1,4-dioxane-2,5-dione. The equations appear as follows:##EQU8## in which R₁, R.sub. 2, R₃ and R₄ are each hydrogen, alkyl, arylor arylalkyl and which are chosen so that R₁ and R₂ are not the same asR₃ and R₄ and at least one of R₁ and R₃ has at least one carbon atom. Xis a halogen or R-C-O-,

or RSO₂ O-- where R is H, alkyl or aryl or aralkyl and the catalyst Afor the first step is a strongly acidic catalyst such as concentratedsulfuric acid, p-toluene sulfonic acid, a strongly acidic ion-exchangeresin or other material which effectively acts as a strong acid. Thereagent B for the second step is conveniently a trialkylamine, such astriethylamine, but may be sodium methylate in methyl alcohol, pyridineor a strongly basic ion-exchange resin. For clarity, a trialkylamine isshown as reagent B in the equation above. In the ring-closing step, stepthree, heat is usually sufficient in the presence or absence of asolvent or diluent.

In view of the well known propensity for α-hydroxyalkanoic acids ingeneral to cyclize or polymerize and then depolymerize or open the ring,it would be expected that unsymmetrical 1,4-dioxane-2,5-diones wouldpolymerize, depolymerize and split to form symmetrical components whichcould permit the formation of long blocks of similar units in the finalpolymer. Fortunately, it is found that such randomization does not occurand that regularity of the acid units in the polymer occurs so that thecharacteristics can be adapted and tailored to specific uses andreproducibly obtained.

Because of optical activity that can occur if R₁ and R₂ are different orif R₃ and R₄ are different, various stereo isomeric components may beobtained and used. It is particularly convenient to use L- or D- orD,L-lactic acid as a starting material. The optically active forms givedifferent melting points and changes in physical characteristics. It isoften convenient to use L-lactic acid as a starting material in whichcase the polymer contains units with the L-configuration. For instance,chloroacetic acid and L-lactic acid may be used as starting materials togive the L form of 3-methyl-1,4-dioxane-2,5-dione.

Other methods of preparing unsymmetrical 1,4-dioxane-2,5-diones include:(a) Cocodensation of two different alpha-hydroxy acids A and B, withremoval of water to form a low-molecular weight random copolymer, andthen heating this copolymer with a transesterification catalyst to forma mixture of cyclic dimers. The desired unsymmetrical cyclic dimer isisolated by fractional distillation. (b) Glycolide is chlorinated togive 3-chloro-1,4-dioxane-2,5-dione and and this is treated with a metalalkyl or metal aryl to give 3-alkyl or 3-aryl-1,4-dioxane-2,5-dione.

In general, the surgical uses of the polymers produced in accordancewith the present invention are similar to those previously taught forpolyglycolic acid. These uses are extremely varied.

For clarity and explanation, certain terms are defined andrepresentative uses given for the novel polymers.

A "filament" is a single, long, thin flexible structure of anon-absorbable or absorbable material. It may be continuous or staple.

"Staple" is used to designate a group of shorter filaments which areusually twisted together to form a longer continuous thread.

An absorbable filament is one which is absorbed, that is, digested ordissolved, in living mammalian tissue.

A "thread" is a plurality of filaments, either continuous or staple,twisted together.

A "strand" is a plurality of filaments or threads twisted, plaited,braided, or laid parallel to form a unit for further construction into afabric, or used per se, or a monofilament of such size as to be woven orused independently.

A "fabric" is a three dimensional assembly of filaments, which may bewoven, knitted, felted or otherwise formed into a flexible sheet havingtwo layer dimensions and a thinner thickness dimension. A fabric may becut to a desired size before or at the time of use.

Except where limited specifically or by context, the word fabricincludes both absorbable and non-absorbable cloth, or a fabric or cloththat is partially of absorbable polymer.

A "dressing" is a woven, knitted, felted or braided fabric, of at leastone layer, which is designed to protect a wound and favor its healing.As used herein, the term dressing includes bandages insofar as theycontact the wound itself. The dressing may be entirely internal.

A "bandage" is a strip of gauze, or other material used to hold adressing in place, to apply pressure, to immobilize a part, toobliterate tissue cavities or to check hemorrhage. Except insofar as thebandage comes in contact with a wound, or the exudate from a wound,there is no need for the bandage to be of absorbable polymer. If thebandage may be in a position where absorbability by living tissue of atleast part of the bandage is desirable, at least that part should be ofabsorbable polymer.

A "respository" is a composite of a medicament and a carrier whereby themedicament is placed in a desired location, and released slowly by thecarrier so that the effective therapeutic action of the medicament isextended. Slowly digestible drug release devices, including pills andpellets, may be inserted subcutaneously, or orally, or into any bodycavity where slowed release of the medicament is desired. Digestiblecarriers are preferred. The digestion may be in the intestinal tract orin tissue depending on the desired administrative site. An absorbablepolymer is chosen whose digestive rate releases the medicament at adesired rate.

The dressing may be in part directive of growth, as, for example, innerve tissue, which grows slowly, and as a result has regenerationimpaired by the more rapid growth of scar tissue which can block thegrowth of the nerve tissue. With a wrap-around sheath of absorbablepolymer fabric or a split or solid tube used to support, place, hold andprotect; regeneration of nerve tissue and function is greatly aided.Other factors may inhibit regeneration of nerve tissue or function, butwith the exclusion of scar tissue, such other factors may be separatelytreated.

For different purposes and in different types of tissue the rate ofabsorption may vary. In general, an absorbable suture or solid loadbearing prosthesis should have as high a portion of its originalstrength as possible for at least three days, and sometimes as much asthirty days or more, and preferably should be completely absorbed bymuscular tissue within from 45 to 90 days or more depending on the massof the cross-section. The rate of absorption in other tissues may varyeven more.

For dressings, strength is often a minimal requirement. Some dressings,as for instance, on a skin abrasion, may need strength for only a fewhours until a scab forms, and rapid decrease of strength and absorptionis an advantage so that when the scab is ready to fall off, the dressingdoes not cause a delay. For burns, and larger lesions, strength andreinforcement may be desired for a longer period.

In common with many biological systems, the requirements are notabsolute and the rate of absorption as well as the short-term strengthrequirement varies from patient to patient and at different locationswithin the body, as well as with the thickness of the section of thepolymer.

The absorbable polymer may be formed as tubes or sheets for surgicalrepair and may also be spun as thin filaments and woven or felted toform absorbable sponges or absorbable gauze, or used in conjunction withother compressive structures as prosthetic devices within the body of ahuman or animal where it is desirable that the structure have short-termstrength, but be absorbable. The useful embodiments include tubes,including branched tubes or Tees, for artery, vein or intestinal repair,nerve splicing, tendon splicing, sheets for tying up and supportingdamaged kidney, liver and other intestinal organs, protecting damagedsurface areas such as abrasions, particularly major abrasions, or areaswhere the skin and underlying tissues are damaged or surgically removed.

In surgical techniques involving internal organs, hemorrhage may be amajor problem. Some of the organs have such tissue characteristics thatit is very difficult to use sutures or ligatures to prevent bleeding.For example, the human liver may suffer traumatic damage or exhibittumors or for other reasons require surgery. In the past it has beenvery difficult to excise part of the liver or to suture the liverwithout the combined problems of the sutures cutting out and hemorrageat the surface causing such major complications as to either preventsurgery or cause an unfavorable prognosis.

It is now found that a sponge or pad or velour of the present absorbablepolymer may be used to protect the surface and permit now feats ofsurgical intervention. For instance, filaments may be formed into awoven gauze or felted sponge or a velour, preferably the construction isfairly tight by textile standards, and such sponge may be placed on thesurface of the bleeding organ such as the liver or a lung with eithergentle suturing or with ties in the nature of ligatures to hold theelement in position with a certain amount of body fluids flowing intothe sponge and being absorbed, which results in hemostasis andprevention of further loss of body fluids. If a liver or lung is sorepaired, the organ may be replaced in the body cavity and the woundclosed.

Where surgically useful, the sponge or fabric can be used as a bolsterto prevent a sature from cutting out. For instance, if the liver is tobe sutured, an absorbable polymer pad can be placed on the surfaces toreinforce the tissue and prevent the suture from cutting into ratherthan retaining the tissue. Such pads of gauze or felt protect tissuefrom cutting.

Absorbable pads, bandages or sponges are extremely useful in surgicaltechniques in which it is the intent to remove the major portion or allof such sponges, felt or pads but, through inadvertence or accident,part of it may remain. For instance, in a surgical operation one of theproblems which arises is the lint from cotton sponges remaining in thewound. If absorbable polymer sponges are used, any small fragments whichare accidentally displaced are absorbed without incident and even if asponge is left in the wound, the deleterious effects are minimal.

The use of a synthetic absorbable polymer as a sponge or pad isparticularly advantageous for surface abrasions. In the past it has beennecessary to put on a dressing and avoid having the non-absorbabledressing grow into the tissue at all costs. If elements of an absorbablepolymer gauze are beneath the regenerating tissue level, the tissue willregenerate and absorb the polymer with the residual polymer in the scabfalling off when the scab is displaced.

The dressing that contacts tissue should be sterile. A strippablesterile package is a convenient storage system to maintain sterilitybetween the time of manufacture and time of use.

Even in cosmetic surgery or skin surgery, when in the past it has beenquite customary to use silk sutures and, after the tissue is regeneratedsufficient to be self retaining, remove the sutures so that they do notleave scars, the use of synthetic absorbable polymer sutures now permitsimplantation of sutures through the skin with the part below the skinsurface being absorbed and the part above the skin surface falling off.The resulting minimal degree of scarring at the skin surface is highlyadvantageous.

In surgery various tissues need to be retained in position duringhealing. Defects and wounds of the abdominal wall, chest wall and othersuch tissues need to be reconstructed. For a hernia, a permanent spliceor reinforcement is often desired as shown in Usher, U.S. Pat. No.3,054,406, SURGICAL MESH, or U.S. Pat. No. 3,124,136, METHOD OFREPAIRING BODY TISSUE. For some surgical procedures, a temporaryreinforcing is desired to provide strength while body tissues arehealing; and after the body tissues have assumed the load, foreigncomponents are no longer desired. Tissue retention using the generaltechniques disclosed in the Usher patents, supra, are readilyaccomplished using either an absorbable synthetic polymer monofilamentor polyfilament fabric or mesh or by using a nonabsorbable material suchas polyethylene or polypropylene or polyester woven as a bicomponentmesh or kit with an absorbable synthetic polymer. The use of abicomponent fabric has the advantage of giving additional early strengthfor holding the tissues in position during initial regeneration with theabsorbable portions being absorbed, thus permitting body tissues toinvade and reinforce the permanent mesh.

In common with other surgical procedures, it is often desirable that abicomponent structure be used which provides the spacing desired fornon-absorbable elements, with the absorbable synthetic polymer elementholding the structure in a desired geometrical configuration at thestart of the healing process. As the element is absorbed, regeneratingtissue invades and replaces the dissolved synthetic polymer so that thenon-absorbed element is left in a desired configuration, interlaced withliving tissue in a stress-transferring relationship.

The choice of a non-absorbable reinforcement, a partially absorbablereinforcement, or a completely absorbable reinforcement is a matter ofsurgical judgment, based upon the condition of the patient, the bodystructure under treatment, and other medical factors.

For instance, a synthetic absorbable polymer sponge may be used in acavity after tooth extraction to stanch the flow of blood. The sponge iseither absorbed by regenerating tissue, or disintegrates into the mouth,permitting improved recovery after extractions.

The medical uses of the polymers of the present invention include, butare not necessarily limited to:

A. Absorbable polymer alone

1. Solid Products, molded or machined

a. Orthopedic pins, clamps, screws and plates

b. Clips (e.g., for use as hemostat)

c. Staples

d. Hooks, buttons and snaps

e. Bone substitute (e.g., mandible prosthesis)

f. Needles

g. Non-permanent intrauterine devices (spermicide)

h. Temporary draining or testing tubes or capillaries

i. Surgical instruments

j. Vascular implants or supports

k. Vertebral discs

l. Extracorporeal tubing for kidney and heart-lung machines

2. Fibriller Products, Knitted or woven, including velours

a. Burn dressings

b. Hernia patches

c. Absorbent paper or swabs

d. Medicated dressings

e. Facial substitutes

f. Gauze, fabric, sheet, felt or sponge for liver hemostasis

g. Gauze bandages

h. Dental packs

i. Surgical sutures

3. Miscellaneous

a. Flake or powder for burns or abrasions

b. Foam as absorbable prosthesis

c. Substitute for wire in fixations

d. Film spray for prosthetic devices

B. Absorbable polymer in Combination with other Products

1. Solid Products molded or machined

a. Slowly digestible ion-exchange resin

b. Slowly digestible drug release device (pill, pellet) as a repository,oral or implanted or intravaginal

c. Reinforced bone pins, needles, etc.

2. Fibrillar Products

a. Arterial graft or substituents

b. Bandages for skin surfaces

c. Burn dressings (in combination with other polymeric films)

d. Coated sutures (i.e., a coating on a suture of this polymer)

e. A coating of the present polymer on a suture of other material

f. A two component suture, one being the present polymer, the componentsbeing spun or braided toether

g. Multicomponent fabrics or gauzes, the other component of which may benon-absorbable, or more rapidly absorbable.

The synthetic character and hence predictable formability andconsistency in characteristics obtainable from a controlled process arehighly desirable.

One convenient method of sterilizing synthetic absorbable polymerprosthesis is by heat under such conditions that any microorganisms ordeleterious materials are rendered inactive. Another common method is tosterilize using a gaseous sterilizing agent such as ethylene oxide.Other methods of sterilizing include radiation by X-rays, gamma rays,neutrons, electrons, etc., or high intensity ultrasonic vibrationalenergy or combinations of these methods. The present syntheticabsorbable polymers may be sterilized by any of these methods, althoughthere may be an appreciable but acceptable change in physicalcharacteristics.

Controlled release rates are very desirable. Some drugs are injectedwith the intention that the faster the drug is absorbed, the better.Others need to be emplaced under such conditions that the maximumconcentration released is within desired limits, and yet the drug ismade available over an extended period of time so that a singleimplantation can last for whatever length of time is desired for aparticular medical procedure. For instance, as a birth control pill, theblood levels of certain steroids are to be maintained at a low level forprolonged periods. The steroid may be dissolved in chloroform, thepresent polymers added, the mixture dried and tabletted. The polymer,its molecular weight and hydrolytic history affect the relative rate ofdrug release and absorption of the carrier.

For contraceptive purposes, an effective storage bank may be desiredwith a prolonged release time. The medicament containing absorbablepolymer may be shaped and used as an intrauterine contraceptive device,having the advantages of both shape and the released medicament, andadditionally an inherently limited effective life. With other steroidsused for the treatment of pathological conditions, the choice may bethat the entire dosage is released uniformly over a period of from 1 to30 days, or so. For other drugs the release period desired may be evenmore widely variable. For some antibiotics an effective concentrationfor 1 or 2 days is preferred for control of some pathogens.

Additional materials such as silicones may be coated upon the polymerrepository where it is desired that the release rate be further delayed.For instance, there are pathological conditions under which the releaseof a drug or hormone may be desired for the remaining life of a subject.

Sterility is essential in the subcutaneous implants, and desirable inoral forms. If the medicament is adaptable to radiation, heat, orethylene oxide sterilizing cycles, such may be used. For more labilemedicaments, the absorbable repository forms are made using steriletechniques from sterile components, or a sterilization procedure ischosen which is compatible with the medicament characteristics.

Other substances may be present, such as dyes, antibiotics, antiseptics,anaesthetics, and antioxidants. Surfaces can be coated with a silicone,beeswax, and the like to modify handling or absorption rate.

The absorbable polymer can be spun into fibers and used to form strands.Fibers of about 0.002 inch diameter are particularly convenient forfabrication. Sheets, or tubes from these absorbable polymer are wrappedaround nerves, traumatically severed, to protect such nerves frominvasive scar tissue growth, while the nerve is regenerating.

The ends or edges of mono-component or bi-component fabrics containingabsorbable polymer may be rendered rigid by molding such edges, with orwithout additional solid absorbable polymer to a desired configuration.It is often easier to insert and retain a flexible fabric prosthetictube if the end of the tube is of a size and shape to be inserted intothe severed end of a vessel.

Becoming of increasing interest and importance is the implantation ofcosmetic devices. For example, some women, due to partial surgicalremoval of breast tissue because of malignancies or traumatic injuries,are left with smaller breasts than are considered desirable.Additionally, some women are not as well naturally endowed as may berequired by the styling trends or fashion at a particular time. In thepast, among the first surgical contributions to inflation wereinjections of silicones. The silicones enlarge the appearance of thebreast, but inherently remain shiftable and hence the silicone is apt tomigrate from the desired location to some other less strategic area.

A non-migrating prosthetic implantation has been used which consists ofa plastic sponge or a plastic bag partially filled with a liquid havinga viscosity adjusted to simulate that of natural tissue. The bag isimplanted through a slit under the breast, to raise the mammary tissueaway from the underlying chest wall which permits surgicalreconstruction which has a very natural appearance and resilience. SeeU.S. Pat. 3,550,214 for surgical details.

A difficulty that is encountered is the possibility of displacement ofsuch an implanted bag from the location of choice from the effects ofgravity or pressure.

If the bag to be used is constructed from a physiologically inertmaterial such as polypropylene or a silicone film, the bag can be formedwith a surface roughness in which, through loops, or fusion of filamentsof polypropylene or other material there is formed a bag to which thenon-absorbable filament are attached. If tissue absorbable polymerfibers as a bi-component material are stitched, woven, felted orotherwise formed into such appendant structures, the elements may bereadily emplaced and the tissue absorbable polymer portions aredissolved out with naturally occurring tissue replacing the absorbablepolymer and thus becoming intermeshed with the elements attached to theprosthetic bag which interlocks the bag in location in the body tissues,primarily the chest wall, and hence the implanted prosthetic device isfirmly locked into the tissues and protected from accidentaldisplacement, maintaining a desired configuration with comfort to thepatient.

In one embodiment, the implanted prosthetic device is an implantable bagcontaining viscous liquid therein, which may be a single cell or asub-divided cell, with a puncturable area in a selected location so thatafter implantation, a hypodermic needle may be used to puncture throughthe skin and intervening tissues, the puncturable area and into the mainvolume of the prosthetic device which permits hypodermic removal oraddition of inflating liquid so that with a minimum inconvenience, timeand expense, the enhancing volume may be modified with changing fashionsor the desires of the user.

A similarly constructed element using the same conjoint bi-componentdisplacing technique is useful to fill out other areas in which externaltissue contours are to be changed. For example, an individual may havebeen involved in an automobile accident or the victim of a tumor andwith the removal of certain tissues, a disfiguring surface configurationremains. By filling in with a prosthetic element of suitable size andshape, the surface configuration can be reconstructed to the greatpsychological benefit of the subject.

Similar, but solid, devices may be implanted in the nose, chin or earsto modify, restore or correct the surface configuration of the subject.In some instances, it is found that the psychological benefit to thesubject far overshadows any surgical risks, costs or inconveniencesresulting from the operative technique.

A bi-component system can be used to aid in retaining implanted devicessuch as internal pacemakers or hearing aids. See U.S. Pat. No.3,557,775, supra, for details of the surgical aspects.

In the case of extensive superficial abrasions, dressings, frequentlygauze, pads or wrappings absorb blood or lymph and present a problembecause the gauze dressings stick to the wound or are infiltrated byregenerated tissue. In the past, it has been customary to changedressings frequently to prevent such infiltration. Removing an adherentdressing can be quite painful.

Extensive surface abrasions such as from sliding on a concrete surfaceafter falling off a motorcycle can be debrided and wrapped with a gauzesynthetic absorbable polymer. The wound shows a tendency to bleed intothe absorbable polymer gauze but the porosity of the gauze aids inrapidly stopping the flow of blood. By using several layers andpermitting the blood to at least partially harden, a minimum amount ofthe absorbable polymer gauze is required and the main protectivedressing is of ordinary cotton gauze wrapped around the injured area. Aminimum of changing the dressing is required. The outer cotton gauze maybe removed for inspection to be sure that infection does not occur, butthe absorbable polymer gauze is allowed to remain in position, andpartly heals into the tissue, and partly remains above the tissue. Fewermanipulative steps aid in preventing the entrance of new pathogens.After healing, the gauze below the new skin surface absorbs in the bodyand the non-absorbed gauze and the scab separate readily.

Detals of representative syntheses are set forth in the followingexamples, in which parts are by weight unless otherwise clearlyindicated.

EXAMPLE 1 Synthesis of 3-methyl-1,4-dioxane-2,5-Dione

One mole of chloroacetic acid (94.5 gms.), one mole of D,L-lactic acid(107.0 gms. of 85% water solution), and 8 gms. of Dowex 50W-X ionexchange resin (equivalent to 1 ml. conc. H₂ SO₄), and 200 ml. benzenewere refluxed and the theoretical amount of water collected in aDean-Stark trap. The solution was allowed to cool to room temperatureand the ion exchange resin was filtered off. The benzene was removed ona rotary evaporator with vacuum. The unreacted chloroacetic acid wassublimed out at 0.2 - 0.4 torr. The O-chloroacetyl-D,L-lactic acid wasdistilled at 108°-118°C. at 0.2 - 0.3 torr (b.p. ref: U.S. Pat. No.2,518,456, supra, 113°-118°C. at 0.4 torr,) m.p.: 73°-74°C). Afterrecrystallization from toluene the O-chloroacetyl-D,L-lactic acid has am.p. of 72°-74°C.

3.34 g (0.02 mole) O-chloroacetyl-D,L-lactic acid and 2.02 g. (0.02mole) triethylamine were dissolved in 670 ml. dimethyl formamide. Thesolution was heated to 100 ± 5°C. for six hours and allowed to cool toroom temperature. The solvent was distilled off under vacuum yielding areddish colored semisolid residue. The product was removed by extractionwith acetone leaving solid triethylamine hydrochloride.

The acetone extract was evaporated yielding a reddish colored oil whichslidified on standing to a reddish yellow solid. It was recrystallizedby dissolving in warm isopropanol and cooling to -25°C. TheD,L-3-methyl-1,4-dioxane-2,5-dione had a melting point of 64°-65°C. (0.7g). It was further purified by sublimation at 0.01 torr. at 50°-60°C.The yield was 0.3 g., m.p. 63.8°-64.2°C. % Carbon found was 46.57 vs.46.10 calc'd. % Hydrogen found was 4.73 vs. 4.60 calc'd. The protonnuclear magnetic resonance spectrum of this product in CDCl₃ gave thefollowing absorptions where δ (delta) = ppm shift downfield fromtetramethyl silane reference absorption; doublet, 3 protons (1.66, 1.72delta, J = 6 H_(z)); quartet 1 proton ((4.97), 5.03, 5.10, 5.16 delta, J= 6-7 H_(z)); quartet, 2 protons (4.78, 4.94, 4.96, 5.12 delta, J = 16H_(z)), confirming the structure as 3-methyl-1,4-dioxane-2,5-dione. Theproduct is essentially racemic as would be expected.

NMR Spectrum of 3-methyl-1,4-dioxane-2,5-dione

The proton nuclear magnetic resonance spectrum of a chemical compoundreveals the number of protons in the molecule that are located indifferent chemical environments by a series of absorption peaks whoseareas are proportional to the number of protons. (See, for example, F.A. Bovey, High Resolution NMR of Macromolecules, Chapter 1, AcademicPress, N.Y., 1972). Furthermore, the absorptions are split into multiplepeaks by neighboring protons in characteristic ways which further aid inassigning peaks to specific chemical structures. (Bovey, pg. 30-32). Thespectrum of 3-methyl-1,4-dioxane-2,5-dione: ##EQU9## obtained on a 100megaherz Varian HA-100 spectrometer shows the following absorptionsgrouped to indicate the splittings of single absorptions intomultiplets.

                  TABLE I                                                         ______________________________________                                        Position of Splitting  Relative                                               Line Delta (δ)                                                                      (Herz)     Area     Assignment                                    ______________________________________                                        1.66                                                                                       6 H.sub.z 3        3 H.sup.a protons                             1.72                                                                          5.03                                                                          5.10                                                                                       6 H.sub.z           H.sup.b protons                              5.16                                                                          4.78                                                                                      16 H.sub.z 3         H.sup.c or H.sup.d                           4.94                                                                          4.96                                                                                      16 H.sub.z           H.sup.c or H.sup.d                           5.12                                                                          ______________________________________                                    

A H atom attached to a carbon bearing an oxygen atom, such as H^(a), isexpected to absorb at 1.3-2 delta (Bovey pg. 29). The absorption shouldbe split into two lines separated by 2-13 Herz. (Bovey pg. 36). Thevalues observed are 1.69 delta (average of doublet) and 6 Herz.

A proton in the environment of H^(b) should absorb at delta than##EQU10## or CH₃ --C-- because it is influenced by both the ##EQU11##and --O-- groups, each of which causes a downfield shift from CH. H^(b)should be split into 4 lines with a splitting OF 6 H_(z) correspondingto the splitting observed in the CH₃ protons. Actually, only 3 lines areobserved, but the expected position of the fourth line, (5.03-.06)=4.97coincides with another strong line of a different origin. Thus, the 3lines at 5.03, 5.10 and 5.16 delta are assigned to H^(b).

Protons in the environment of H^(c) and H^(d) should absorb at about thesame delta as H^(b) and at first glance H^(c) and H^(d) would appear tohave identical environments and give a single line. Actually, one mustbe somewhat nearer than the other to the CH₃ group on the opposite sideof the ring so the environments differ. The spectrum shows a quartet oflines due to this pair as is expected for two different interactingprotons. The splitting of 16 H_(z) between the first and second linesand between the third and fourth lines is consistent with splittingsobserved between protons on the same atom. (Bovey, pg. 35). Quartets ofthis type are not observed in the spectrum of either glycolide orlactide which are tabulated below for comparison.

                  TABLE II                                                        ______________________________________                                        Compound    Peak Positions                                                    ______________________________________                                        3-methyl-1,4-                                                                             1.66     5.03     4.78                                            dioxane-2,5-                                                                              1.72     5.10     4.94                                            dione                5.16     4.96                                                                          5.12                                            lactide     1.66     4.94                                                                 1.72     5.01                                                                          5.07                                                                          5.14                                                     glycolide                            4.94                                     ______________________________________                                    

Thus, the NMR spectrum of 3-methyl-1,4-dioxane-2,5-dione is consistentwith the assigned structure and inconsistent with any mixture ofglycolide and lactide.

EXAMPLE 2 Homopolymerization of 3-methyl-1,4-dioxane-2,5-dione, at125°C.

In a glass tube was charged 1.0 g. of 3-methyl-1,4-dioxane-2,5-dioneprepared as in Example 1 and 0.80 ml. of an ether solution cotaining 0.-mg. of SnCl₂.2H₂ 0 per ml. The ether was vaporized off, and the tubesealed under vacuum. The tube was then placed in a 125°C. oil bath for80 hours. The tube was cooled, broken open and the contents dissolved in10 ml. of hexafluoracetone sesquihydrate (HFAS). This solution was addeddropwise to 100 ml. of methanol and the resulting precipitated polymerwas dried in vacuo for two days at room temperature. The resultingpolymer weighed 0.6 g. (67% conversion) and had a melting point bydifferential thermal analysis of 100°C. and an inherent viscosity inHFAS of 0.38 dl/g (0.5 g./100 ml.) at 30°C. The proton NMR spectrummeasured in hexafluoracetone sesquideuterate gave the followingabsorptions where ( δ )delta=ppm shift downfield from tetramethylsilanereference absorption: 5.402, 5.332, 4.904, 1.676, 1.605 delta.

Inherent viscosity as used herein is η inh=ln η rel/c where η rel is theratio of the viscosity of a 0.5%(W/V) solution of the polymer inhexafluoracetone sesquihydrate to the viscosity of that solvent alone,and c = 0.5 grams per 100 ml.

NMR Spectrum of Poly(3-Methyl-1,4-Dioxane-2,5-Dione) The proton nuclearmagnetic resonance spectrum of polymers containing glycolic acid units##EQU12## and lactic acid units ##EQU13## reveals the number of protonswhich exist in each of the different chemical environments in thepolymer chain. For poly(D,L-lactic acid) the methine (.tbd.CH) protonappears as a quartet the center of which is located at 5.286 delta(where delta is the parts per million chemical shift to lower magneticfield from the absorption of the methyl groups in the tetramethyl silanereference standard.) The area of the quartet absorption is one third thearea of the methyl absorption as expected. The quartet structure arisesdue to spin-spin coupling with the protons of the adjoining --CH₃ groupand further substantiates the assignment.

In a copolymer of D,L-lactide and glycolide containing 52 lactic acidunits for each 48 glycolic acid units, two overlapping quartets are seenin the .tbd.CH region with centers located as shown in Table III. Thequartet centered at 5.276 falls close to that in poly(lactic acid)(5.286) and can be assigned to the methine proton in the center lacticacid unit of the --L--L--L-- sequence: ##EQU14## The second quartet inthe copolymer is centered at 5.310, very close to the center of the onlyquartet seen in a 8/92 lactic acid unit/glycolic acid unit copolymerwhere isolated pairs of lactic acid units should predominate. The 5.310quartet can thus be assigned to the center methine proton of either a--GLL-- or --LLG-- sequence: ##EQU15## or ##EQU16##

The spectrum of poly(3-methyl-1,4-dioxane-2,5-dione) prepared as inExample 2 shows a quartet absorption centered at 5.367, significantlyshifted from absorptions assigned to the --LLL--, --GLL-- or --LLG--sequences. The 5.367 absorption can logically be assigned to the centermethine proton of the GLG sequence, which is the only other possiblesequence of three residues. This is the sequence expected to predominateif polymerization of this monomer occurs by successive attack of theactive end group on the least hindered carbonyl group of3-methyl-1,4-dioxane-2,5-dione to yield --G--L--G--L--G--L-- chains. Thepresence of minor amounts of --GLL-- and --LLG-- sequences is not ruledout by the NMR spectra as minor absorption at 5.307-5.310 could bemasked by the principal methine absorption.

Thus, the position of the lactic acid unit methine absorption reflectsthe chemical nature of two neighboring units. As the neighbors changefrom two lactic acid units to one lactic acid unit and then no lacticacid unit, there is a progressive downfield (higher delta) shift of themethine absorption.

                                      TABLE III                                   __________________________________________________________________________                   CHEMICAL SHIFT (DELTA) FOR CENTER OF MULTIPLET                 Polymer        --CH(quartet)  --CH.sub.2 (singlet)                                                                   --CH.sub.3 (doublet)                   __________________________________________________________________________    Poly(lactic acid)        5.286                                                                              --       1.633                                  52/48 mole % copolymer                                                                            5.310                                                                              5.276                                                                              4.908    1.641                                  of lactide and glycolide                                                      8/92 mole % copolymer of                                                                          5.307     4.920    1.639                                  lactide and glycolide                                                         Poly(3,-Methyl-1,4-dioxane                                                                   5.367          4.907    1.643                                  2,5-dione)                                                                    Sequence assignment                                                                          --GLG--                                                                            --GLL--                                                                            --LLL--                                                                  and                                                                           --LLG--                                                   __________________________________________________________________________

EXAMPLE 3 Polymerization of D,L-3-methyl-1,4-dioxane-2,5-dione at 220°c.

To a glass tube was charged 0.5 g. of 3-methyl-1,4-dioxane-2,5-dione and0.1 ml. of an ether solution containing 0.1 mg. of SnCl₂ .2H₂ O per ml,and 0.06 ml. of an ether solution containing 20 mg. of lauryl alcoholper ml. The ether was vaporized off and the tube sealed under vacuum.The tube was placed in an oil bath at 220°C. for 2 hours. The tube wascooled, broken open, and the contents dissolved in 5 ml. HFAS. Thissolution was added dropwise to 50 ml. of methanol and the resultingprecipitated polymer was dried in vacuo for two days at 50°C. Theresulting poly(D,L-3-methyl-1,4-dioxane-2,5-dione) weighed 0.14g. andhad an inherent viscosity in HFAS of 0.65 dl./g. (0.5 g./100 ml.) at30°C.

EXAMPLE 4 Polymerization of D,L-3-methyl-1,4-dioxane-2,5-dione at 180°C.

To a glass tube was added 2.0 g. D,L-3-methyl-1,4-dioxane-2,5-dione and0.4 ml. of an ether solution containing 0.1 mg. of SnCl₂ .2H₂ O per ml.The ether was vaporized and removed and the tube sealed under vacuum.The tube was placed in an oil bath at 180 ± 5°C. and heated for 24hours. The tube is cooled, broken open and the contents dissolved in 40ml. of hexafluoroisopropanol (HIPA). This solution was added dropwise to400 ml. of methanol and the resulting precipitatedpoly(D,L-3-methyl-1,4-dioxane-2,5-dione) was dried in vacuo for 16 hoursat 50°C. The resulting polymer weighed 1.65 g. and had an inherentviscosity in HFAS of 0.83 dl/g (0.5 g./100 ml.) at 30°C.

EXAMPLE 5 Extrusion of Poly(D,L-3-methyl-1,4-dioxane-2,5-dione) asMonofilaments

A 0.5 g. sample of the polymer of Example 4 was placed in the barrel (1cm i.d.) of a melt-index apparatus (Custom Scientific) fitted with abottom plug 1 cm. in height and having a 0.5 mm. vertical central hole.A close-fitting weighted piston (4700g) was placed in the barrel whichhad been preheated to 160°C. The monofilament which extruded from thehole had a diameter in the range of 0.002 to 0.006 inches (0.05 to 0.15mm.) and was rather weak. The filaments were drawn by hand to four timestheir original length on a hot plate having a surface temperature of50°-60°C. They become much stronger, showing a tensile strength at breakof 17,000 to 21,000 psi. (1,200-1,470 Kg/cm²).

EXAMPLE 6 Polymerization of D,L-3-methyl-1,4-dioxane-2,5-dione at 180°C.

To a glass tube was added 6.0 g. of D,L-3-methyl-1,4-dioxane-2,5-dioneand 1.2 ml. of an ether solution containing 0.1 mg. of SnCl₂ .2H₂ O perml. The ether was vaporized and removed, and the tube sealed. The sealedtube was placed in an oil bath at 180 ± 2°C. for 4hours, cooled andbroken. The cooled tube contents were dissolved in 120 ml. of boilingacetone and the solution added dropwise to 1200 ml. of methanol. Theresulting precipitated poly(D,L-3-methyl-1,4-dioxane-2,5-dione) wasdried in vacuo for 2 days at 25°C. The resulting polymer weighed 1.4 g.(23% conversion) and had an inherent viscosity in HFAS of 1.19dl/g(0.5g/100ml) at 30°C.

EXAMPLES 7, 8, and 9 Copolymerization ofD,L-3-methyl-1,4-dioxane-2,5-dione with Glycolide

The amounts of D,L-3-methyl-1,4-dioxane-2,5-dione and glycolideindicated in Table IV were combined in glass tubes with 0.80 ml. of anether solution containing 0.1 mg. of SnCl₂ .2H₂ O per ml. and 0.5 ml. ofan ether solution containing 20 mg. lauryl alcohol per ml. The ether wasvaporized and removed and the tubes sealed under vacuum. The tubes wereplaced in an oil bath at 220°C. for 2 hours. The contents of each cooledand broken tube were dissolved in HFAS and precipitated in methanol. Theprecipitated polymer was dried 2 days in vacuo at 50°C.

                  TABLE IV                                                        ______________________________________                                                     Exam-   Exam-     Exam-                                                       ple 7   ple 8     ple 9                                          ______________________________________                                        Mole % D,L-3-  10        25        50                                         methyl-1,4-                                                                   dioxane-2,5-dione                                                             Weight of glycolide                                                           used (g)       3.58      2.96      1.86                                       Weight of D,L-3-                                                              methyl-1,4-dioxane-                                                           2,5-dione used (g)                                                                           0.44      1.10      2.08                                       % Conversion to                                                               Polymer        80        79        25                                         Melting Point,                                                                (Fisher-Johns                                                                 Apparatus)     212°C                                                                            188°C                                                                            132°C                               Inherent Viscosity                                                            in HFAS(0.5 mg./ml.)                                                          30°C    0.45      0.32      0.18                                       Mole % D,L-3-                                                                 methyl-1,4-dioxane-                                                           2,5-dione in Poly-                                                            mer (by NMR)   4.8       16.2      31.7                                       ______________________________________                                    

EXAMPLES 10 and 11 Implantation ofGlycolide/D,L-3-Methyl-1,4-Dioxane-2,5-Dione Copolymer in Rabbits

The copolymers of Examples 7 and 8 (and polyglycolic acid (PGA), 0.89inherent viscosity) were formed into strips at room temperature bydistributing 0.4 g. of powdered polymer in a die 3/4 inch deep by 1/2inch wide by 3 inches long (1.9 × 1.27 × 7.62 cm) and exerting ahydraulic pressure of 16,000 pounds (7,260kg) on the matched plunger for30 seconds by means of a Carver hydraulic press. This large pressedpiece was cut into 4 strips, each approximately 1.5 inches long, 1/4inch wide (3.8 × 0.63 cm.) and weighing approximately 0.1 g. Each stripwas placed in a plastic envelope, vacuum dried, heat sealed, sterilizedwith ethylene oxide overnight and the residual ethylene oxide was pumpedoff. Individual strips were then implanted subcutaneously in rabbits. Atintervals the rabbits were sacrificed and observed for tissue reactionat the implantation site. The extent of absorption was estimatedvisually. Tissue reaction was unremarkable in each case. The estimatedextent of absorption is shown in Table V.

                  TABLE V                                                         ______________________________________                                                    PGA     Exam-     Exam-                                                       Control ple 7     ple 8                                           ______________________________________                                        Mole Ratio of                                                                 Polymer of D,L-                                                               3-methyl-1,4-                                                                 dioxane-2,5-dione/                                                            glycolide     0/100     4.8/95.2  16.2/83.8                                   Absorption at                                                                 15 days       50%       40-50%    <25%                                        Absorption at                                                                 30 days       90-100%   100%      90-100%                                     Absorption at                                                                 45 days       100%      100%      100%                                        ______________________________________                                    

EXAMPLE 12 Implantation of Poly(D,L-3-methyl-1,4-Dioxane-2,5-Dione

Following the procedure of Examples 10 and 11, strips of thepoly(D,L-3-methyl-1,4-dioxane-2,5-dione) of Example 6 were prepared andimplanted in rabbits. Tissue reaction was unremarkable in each case. Theestimated extent of absorption of duplicate samples of these strips andof polyglycolic acid (PGA) control strips is shown in Table VI.

                  TABLE VI                                                        ______________________________________                                                               Poly(D,L-3-                                                                   Methyl-1,4-                                                                   Dioxane-2,5-                                                         PGA      Dione                                                  ______________________________________                                        Absorption at 15 days                                                                         50,50%     0,0%                                               Absorption at 30 days                                                                         85,85%     50,50%                                             Absorption at 45 days                                                                         100,100%   85,100%                                            ______________________________________                                    

EXAMPLE 13 Preparation of O-Chloroacetyl-L-Lactic Acid

Into a 2-liter, 2-necked round bottom flask equipped with a magneticstirrer and a Dean-Stark trap was placed 750 ml. of benzene and 8.0 g.Dowex 50W-X resin. To this suspension 262.2 g. (2.78 mole) ofmonochloroacetic acid was added. The mixture was refluxed until nofurther water was collected.

To this was then added 100 g. (1.11 mole) of crystalline L-lactic acidin ten equal portions at a rate such that a subsequent portion was notadded until the theoretical amount of water was collected from thepreceding portion.

When all water had been collected, heating was discontinued and theresin removed by filtration from the hot solution. The resin was thenwashed with two 50 ml. portions of hot benzene. The washings were addedto the reaction mixture, and the solvent removed in vacuo.

The crude oil which remained was then carefully distilled to removeexcess monochloroacetic acid. The remaining oil was then distilled at95°-105°C./0.05 torr. to give 143.3 g. (77.3'%) ofO-chloroacetyl-L-lactic acid. This was then redistilled, to give 130grams (70.3%) of product, b.p. 94°-100°C./0.05 torr.

    Calculated for ClCH.sub.2                                                                    --C--O--CH--C--OH                                                             ∥|∥                                                OCH.sub.3 O                                                                 Found                                                            ______________________________________                                        C          36.05   35.86                                                      H          4.24    4.41                                                       Cl         21.29   20.74                                                      MW        166.56   173                                                        ______________________________________                                         [α].sub.D.sup.25 = -60° ± 0.7 (C = 1.34, CHCL.sub.3)

Ir peaks 3050 cm.sup.⁻¹, 2975 cm.sup.⁻¹, 1750 cm.sup.⁻¹, 1460 cm.sup.⁻¹,1412 cm.sup.⁻¹, 1378 cm.sup.⁻¹, 1345 cm.sup.⁻¹, 1315 cm.sup.⁻¹, 1183cm.sup.⁻¹, 1135 cm.sup.⁻¹, 1095 cm.sup.⁻¹, 1043 cm.sup.⁻¹, 957cm.sup.⁻¹, 930 cm.sup.⁻¹, 833 cm.sup.⁻¹, 788 cm.sup.⁻¹.

Nmr (cdcl₃, TMS) singlet 9.53 δ, quartet 5.33, 5.26, 5.19, 5.12 δ,singlet 4.16 δ, doublet 1.64, 1.56 δ.

EXAMPLE 14 Preparation of L-3-methyl-1,4-dioxane-2,5-dione 1

Forty-five grams (0.270 mole) of O-chloroacetyl-L-lactic acid wasdissolved in 4500 ml. of amine-free, dry dimethylformamide. To thissolution was added 35.83 ml. (26.0 grams, 0.256 mole) of drytriethylamine. The solution was then heated to 100°C. and kept at thistemperature for four hours. At the end of this time, the heating wasdiscontinued and the solvent removed in vacuo to give an oily-semi-solidresidue.

The residue was treated with one liter of dry diethyl ether and theinsoluble triethylamine hydrochloride filtered off. The ether was thenremoved in vacuo and the oil taken up in 100 ml. of benzene. The benzenewas then extracted with 50 ml. of cold distilled water whose pH wasadjusted to 2.5 with HCl. The benzene solution was then quickly driedover anhydrous sodium sulfate and then dried for one hour over molecularsieves. The sieves were filtered off, washed well with 50 ml. of drybenzene, the combined solvent and washings were then removed in vacuo togive 16.9 grams (51%) of an oil which was crystallized from isopropanolat -20°C. The semi-solid was filtered cold and quickly recrystallizedfrom a minimum volume of boiling isopropanol. Two additionalrecrystallizations from isopropanol gave a white solid,L-3-methyl-1,4-dioxane-2,5-dione, m.p. 38°-39°C., 8.0 grams (24%).

Ir peaks 3450 cm.sup.⁻¹, 1775 cm.sup.⁻¹, 1448 cm.sup.⁻¹, 1378 cm.sup.⁻¹,1345 cm.sup.⁻¹, 1296 cm.sup.⁻¹, 1225 cm.sup.⁻¹, 1195 cm.sup.⁻¹, 1130cm.sup.⁻¹, 1099 cm.sup.⁻¹, 1053 cm.sup.⁻¹, 1036 cm.sup.⁻¹, 958cm.sup.⁻¹, 849 cm.sup.⁻¹, [α]_(D) ²⁵ = -245°(±1.0°) (C=0.988, benzene)

Nmr (cdcl₃,TMS) Quartet (5.00, 5.06, 5.14, 5.20 δ), doublet (4.98, 4.94δ), doublet (1.70, 1.64 δ)

EXAMPLE 15 Preparation of Poly-L-3-methyl-1,4-dioxane-2,5-dione##EQU17##

0.5 grams of L-3-methyl-1,4-dioxane-2,5-dione from Example 14 waspolymerized in the presence of 0.002 weight per cent of stannouschloride dihydrate over a 24 hour period at 180°C. to give 0.5 grams ofpolymer, IV=0.33, and softening point 56°-60°C.

EXAMPLES 16 and 17 Copolymerization of L-3-methyl-1,4-dioxane-2,5-dionewith Glycolide

Polymerization tubes were charged with the quantities of monomersindicated in Table VII and 0.002% SnCl₂.2H 2O by weight based on totalmonomers was added in an ethereal solution. The ether was evaporated andthe tube sealed under vacuum. The tubes were heated in an oil bath for24 hours at 190°C.

The tubes were removed, chilled in dry ice-acetone, cracked open anddissolved in HFAS. The polymer was then precipitated from solution withmethanol, filtered and dried overnight in a vacuum oven.

                  TABLE VII                                                       ______________________________________                                                          Exam-    Exam-                                                                ple 16   ple 17                                             ______________________________________                                        Mole % of L-3-methyl-1,4-                                                     dioxane-2,5-dione   15         25                                             Mole % Glycolide    85         75                                             Gms. L-3-methyl-1,4-                                                          dioxane-2,5-dione   0.5        0.5                                            Gms. glycolide      2.53       1.34                                           Melting Point (Differ-                                                        ential Thermal Analysis                                                       at 10°C./min.)                                                                             196°C.                                                                            175°C.                                  Inherent Viscosity in HFAS                                                    (0.5 mg./ml.) 30°C.                                                                        0.53       0.60                                           Mole % L-3-methyl-1,4-                                                        dioxane-2,5-dione in                                                          Copolymer           7.2        12.4                                           Yield %             78         83                                             ______________________________________                                    

EXAMPLE 18 Preparation of 3,3-dimethyl-1,4-dioxane-2,5-dione

To a flask containing two liters of chloroform, 1 mole of2-hydroxy-isobutyric acid (104.1 gms.) and 2.2 moles of triethylamine(224 gms.), cooled in an ice bath, was slowly added 1 mole ofchloroacetyl chloride (127 gms.). Addition took one hour. The chloroformwas evaporated to yield a reddish semi-solid which was trituratedseveral times with acetone followed by decantation of the reddishacetone extract. The white solid residue was triethylaminehydrochloride. The acetone extracts were combined and concentrated undervacuum to a red oil which was distilled under vacuum. The fractiondistilling at 103°-110°C./0.7-0.9 torr. was collected. This fractionsolidified to a green semi-solid which was recrystallized from isopropylalcohol and then sublimed at 75°C./0.1 torr. to yield 15 grams of whitesolid, m.p. 82°-83°C. This was dissolved in 3000 ml. of benzene at 10°C.and extracted successively with three 300 ml. portions of 0.01 N HClsolution saturated with sodium chloride in a separatory funnel, and thebenzene layer quickly dried by filtration through a bed of anhydroussodium sulfate into a flask containing anhydrous magnesium sulfate.After the removal of the magnesium sulfate by filtration and the benzeneunder vacuum, the solid 3,3-dimethyl-1,4-dioxane-2,5-dione wasrecrystallized from isopropyl alcohol and sublimed at 75°C/0.1 torr. toyield 13 grams of solid, m.p. 85°-86°C., % C found = 50.00 vs. 50.00calculated, % H found = 5.52 vs. 5.60 calculated.

The proton NMR spectrum of this sample in CDCl₃ gave the followingabsorptions where δ = ppm shift downfield from the tetramethylsilanereference absorption: singlet, 6 protons at 1.72 δ and singlet, 2protons at 5.02 δ.

EXAMPLES 19, 20 and 21 Copolymerization of Glycolide and3,3-Dimethyl-1,4-dioxane-2,3-dione

To 3 glass tubes were added the amounts of glycolide and3,3-dimethyl-1,4-dioxane-2,5-dione indicated in Table VIII. To each tubewas added 1.2 ml. of an ether solution of SnCl₂.2H₂ O (0.1 mg./ml.) and0.75 ml. of an ether solution of lauryl alcohol (10 mg./ml.). The etherwas evaporated off, and tubes were evacuated and sealed, then heated fortwo hours at 220°C. in an oil bath. After cooling and breaking, the tubecontents were dissolved in 20 ml. of hexafluoroacetone sesquihydrate pergram of recovered solid. The polymer solution was added to 10 times itsvolume of methanol. The precipitated polymer was then extracted for twodays in a Sohxlet extractor with acetone. The undissolved polymer wasvacuum-dried at 50°C. for 24 hours.

                  TABLE VIII                                                      ______________________________________                                                        Exam-  Exam-    Exam-                                                         ple 19 ple 20   ple 21                                        ______________________________________                                        (A) Glycolide, gms.                                                                             5.27     4.60     3.95                                      (B) 3,3-Dimethyl-1,4-                                                         dioxane-2,5-dione 0.74     1.45     2.05                                      Mole ratio (A)/(B) in feed                                                                      90/10    80/20    70/30                                     % Conversion      82       76       64                                        Inherent Viscosity (I.V.)                                                                       0.54     0.45     0.44                                      Mole % B in polymer                                                                             2.1      4.5      6.0                                       ______________________________________                                    

EXAMPLE 22 Copolymerization of D,L-Lactide withD,L-3-Methyl-1,4-Dioxane-2,5-Dione in 10/10 Mole Ratio

To a polymerization tube was added 0.54 grams ofD,L-3-methyl-1,4-dioxane-2,5-dione (0.00415 mole) and 5.41 g. ofD,L-lactide (0.0376 mole), 1.20 ml. of an ether solution of SnCl₂.3H₂ O(0.1 mg./ml.) and 0.75 ml. of an ether solution of lauryl alcohol (10mg./ml.). The ether was vaporized and removed. The tube was evacuated,sealed and heated for 24 hours at 180°C. The cooled tube contents weredissolved in boiling acetone and the resulting solution was added tomethanol. The resulting solid was collected and vacuum dried at 50°C.for 24 hours. The conversion of monomers to polymer was 79% by weightand the polymer inherent viscosity was 1.36. The mole % ofD,L-3-methyl-1,4-dioxane-2,5-dione units in the polymer was 7.9 by NMR.

EXAMPLE 23 Copolymerization of D,L-Lactide withD,L-3-Methyl-1,4-Dioxane-2,5-Dione in 30/20 Mole Ratio

To a polymerization tube was added 1.21 g. ofD,L-3-methyl-1,4-dioxane-2,5-dione (0.00931 mole) and 4.86 g. ofD,L-lactide (0.0338 mole). The procedure was then identical to Example22. The conversion of monomers to polymer was 74% by weight, and thepolymer inherent viscosity was 1.24. The polymer contained 14.7 molepercent of units derived from D,L-3-methyl-1,4-dioxane-2,5-dione by NMR.

EXAMPLE 24 Copolymerization of L-Lactide with D,L-3-Methyl-1,4-Dioxane-2,5-Dione in 90/10 Mole Ratio

Example 22 was repeated substituting L(-) lactide for D,L-lactide.Conversion was 78%, inherent viscosity 0.73 and the polymer contained7.6 mole % of units derived from D,L-3-methyl-1,4-dioxane-2,5-dione byNMR.

EXAMPLE 25 Copolymerization of L-Lactide withD,L-3-Methyl-1,4-Dioxane-2,5-Dione in 30/20 Mole Ratio

Example 23 was repeated substituting L(-)-lactide for D,L-lactide.Conversion was 75%, inherent viscosity 0.61 and the polymer contained10.2 mole % of units derived from D,L-3-methyl-1,4-dioxane-2,5-dione byNMR.

EXAMPLE 26 Preparation of C-Chloroacetyl-L-Lactic Acid

A mixture of 57.6 grams (0.4 mole) of sublimed L-lactide, 378.0 grams(4.0 mole) of monochloroacetic acid and 2.8 grams of antimony trioxidewas heated in an oil bath for 8 hours at 180°C., then for 24 hours at130°C., and finally for five hours at 185°C. The excess monochloroaceticacid was then distilled off in vacuo and the O-chloroacetyl-L-lacticacid produced distilled at 90°-110°C./0.05 torr. to give 109.3 grams(82%) of product. The product was then slowly redistilled at94°-100°C./0.05 torr. to give 100.5 grams (75.4%) ofO-chloroacetyl-L-lactic acid, identical to that prepared from L-lacticacid and monochloroacetic acid.

If 3.1 grams of titanium dioxide is used in place of antimony trioxide,the yield is 69.2 grams of product (51.9%). Tetraisopropyl titanate mayalso be used as a catalyst.

EXAMPLE 27 Preparation of O-Chloroacetyl-D,L-lactic acid fromPoly-D,L-Lactic Acid

530.1 gms. (5.55 mole) of monochloroacetic acid, 100 gms. (1.39 equiv.)of poly-D,L-lactic acid and 1.5 gms. of antimony trioxide was heatedwith stirring at 160°C. for twenty-four hours. The excessmonochloroacetic acid was then distilled off in vacuo and the productdistilled at 85°-100°C/0.075 torr. to give 122.5 gms. (53%) ofO-chloroacetyl-D,L-lactic acid. The material so recovered was identicalto that prepared from D,L-lactic acid and monochloroacetic acid.

EXAMPLE 28 Preparation of D,L-3-Methyl-1,4-Dioxane-2,5-Dione fromGlycolic Acid and D,L-Lactic Acid

To 543 g. of 70% aqueous solution of glycolic acid was added 276 g. ofan 85% aqueous solution of D,L-lactic acid. This mixture was heated in adistillation apparatus at atmospheric pressure until water had ceased todistill. Then, 6 g. of antimony trioxide was added and heating wascontinued at 10 torr. until 350 g. of distillate was obtained (headtemperature range 120°-180°C). This distillate was refractionated usinga Vigreaux column at 10 torr. to give 40 g. of fraction A (b.p.114°-140°C.) and 160 g. of fraction B (b.p. 142°-153°C.). Fraction Bpartially solidified at 5°C. and was recrystallized from 320 ml. ofisopropyl alcohol/

The recrystallized material was further fractionated using a Vigreauxcolumn to yield the fractions shown in Table IX. The fractions wereanalyzed by a gas chromatographic method.

                                      TABLE IX                                    __________________________________________________________________________    Fraction                                                                           Weight                                                                            B.P.   Product Composition                                                                       (Weight Percent)                                  Number                                                                             grams                                                                             (10 Torr.)                                                                           Glycolide                                                                           Lactide                                                                             D,L-M.D.D.                                        __________________________________________________________________________    1    20  142-144°C.                                                                     8    22    70                                                2    54  144-146                                                                              10    13    77                                                3    10  146-148                                                                              17     7    76                                                __________________________________________________________________________

Example 29 Preparation of D,L-3-Methyl-1,4-Dioxane-2,5-Dione fromGlycocolic Acid and D,L-Lactic Acid

Example 28 is repeated until Fraction B is obtained by distillation.This fraction is then fractionated in a high-efficiency distillationapparatus to obtain D,L-3-methyl-1,4-dioxane-2,5-dione with a puritygreater than 99 percent as measured by gas chromatography.

The choice of L-, D-, or D, L- components in the feed to thepolymerization determines the optical activity of the units in thepolymer. The properties tend toward those resulting from greatercrystallinity if a single optical isomer is used in the polymer.

The rate of other absorption in living mammals is affected by thehydrolytic history of the polymers before implantation, the molecularweight, and the size and shape of the implanted polymer, as well as thechemical composition of the polymer. In general, subject to the effectof these ether variables, the higher proportion of glycolic acid units,the more rapid the absorption. The drier the polymer is kept, the slowerthe absorption, and the higher the molecular weight, the stronger thepolymer.

The use of the present homopolymers and co-polymers permits an increasein the range of absorption characteristics available for surgicaldevices.

We claim:
 1. A method of closing a wound of living tissue whichcomprises:sewing the edges of the wound with a surgical sutureconsisting of at least one filament of polymer containing more than 2%by weight of recurring units of the formula: ##EQU18## and the remainingunits are ##EQU19## and ##EQU20## wherein R₁ and R₂ are not the same asR₃ and R₄, R₁ has at least one carbon atom, and R₁, R₂, R₃, R₄, R₅, R₆,R₇ and R₈ are separately selected from the group consisting of hydrogen,and the radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl,cyclohexyl, and phenyl, embedding the suture in living tissue andleaving the suture in said tissue until said suture is absorbed by thetissue during the healing process.
 2. The method of claim 1 in which thepolymer has the formula: ##EQU21## where n is such that the weightaverage molecular weight is at least about 5,000.
 3. The method of claim1 in which the polymer contains more than 2 mole % of recurring units ofthe formula: ##EQU22## the remaining units being ##EQU23## where R₁ isCH₃ -- or H --.
 4. A method of retaining living tissue in a desiredlocation and relationship during a healing process whichcomprises:positioning and emplacing living tissue with a surgicalelement of polymer containing more than 2% by weight of recurring unitsof the formula: ##EQU24## and the remaining units are ##EQU25## and##EQU26## where R₁ and R₂ are not the same as R₃ and R₄, R₁ has at leastone carbon atom, and R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are separatelyselected from the group consisting of hydrogen, and the radicals methyl,ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl, and phenyl,embedding said element in living tissue andleaving said element in saidtissue until said element is absorbed by the tissue during the healingprocess, the element retaining a high proportion of its originalstrength for at least three days and being substantially absorbed inabout six months when the living tissue is muscular tissue, and aproportionate time in other tissues.
 5. The method of claim 4 in whichthe polymer has the formula: ##EQU27## where n is such that the weightaverage molecular weight is at least about 5,000.
 6. The method of claim4 in which the polymer contains more than 2 mole % of recurring units ofthe formula: ##EQU28## the remaining being ##EQU29## where R₁ is CH₃ --or H --.